The overarching canonical role of members of the diverse FGF superfamily in the adult is coordination of tissue homeostasis through autocrine and paracrine growth-promoting signaling controlled by matrix heparan sulfate. With the loss of affinity for heparan sulfate and gain of selectivity for the FGFR1-KLB complex that predominates in mature adipocytes, FGF21 has evolved as an inter-organ stress signal to adipocytes for negative regulation of systemic and cellular metabolic stress. This concept may also apply to evolution of other endocrine FGFs referred to as the FGF19 subfamily. The inter-organ crosstalk between ileal FGF19 and liver FGFR4-KLB is a negative regulatory mechanism of postprandial bile acid levels serving to prevent stress and damage resulting from exposure to prolonged and elevated levels of bile acids (58). Similarly, the negative regulation of mineral re-absorption levels signaled by the crosstalk between bone FGF23 and kidney FGFR1-KL (59) may limit potential stress and damage from mineral overload. The effects of the FGF19 subfamily are pleiotropic and complex on both local tissue and organism levels. Detailed dissection of the action of each endocrine FGF in inter-organ
